Primary Nucleation of Polymorphic α-Synuclein Dimers Depends on Copper Concentrations and Definite Copper-Binding Site

TL;DR

This study reveals how copper concentrations and a specific copper-binding site influence the formation of harmful α-synuclein dimers linked to Parkinson's disease.

Contribution

The paper introduces new molecular mechanisms showing how copper concentration and binding sites affect α-synuclein dimer nucleation.

Findings

High and low copper concentrations lead to distinct α-synuclein dimer structures at atomic resolution.

Copper binding at specific sites modulates the primary nucleation pathways of α-synuclein.

The findings suggest a strategy to control toxic amyloid formation in neurodegenerative diseases.

Abstract

The primary nucleation process of α-synuclein (AS) that forms toxic oligomeric species is the early stage of the pathological cause of Parkinson’s disease. It is well-known that copper influences this primary nucleation process. While significant efforts have been made to solve the structures of polymorphic AS fibrils, the structures of AS oligomers and the copper-bound AS oligomers at the molecular level and the effect of copper concentrations on the primary nucleation are elusive. Here, we propose and demonstrate new molecular mechanism pathways of primary nucleation of AS that are tuned by distinct copper concentrations and by a specific copper-binding site. We present the polymorphic AS dimers bound to different copper-binding sites at the atomic resolution in high- and low-copper concentrations, using extensive molecular dynamics simulations. Our results show the complexity of the primary nucleation pathways that rely on the copper concentrations and the copper binding site. From a broader perspective, our study proposes a new strategy to control the primary nucleation of other toxic amyloid oligomers in other neurodegenerative diseases.

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